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- W4313365540 abstract "Abstract We previously showed that a class I histone deacetylase (HDAC) inhibitor, entinostat (ENT), dramatically improves CD8 T cell-mediated control of TS/A murine mammary tumors, but only when given in a precise window. If given too early ENT halts initial T cell activation and expansion and has no effect if given too late— once T cells start becoming dysfunctional. This led us to hypothesize that HDAC inhibition can maintain CD8 T cells in a less differentiated state that enhances effector and proliferative capacities. To test this, we first treated TS/A tumor-bearing mice with ENT and performed single cell RNA-sequencing on sorted tumor-infiltrating CD8 T cells. Relative to vehicle, ENT treated samples clustered separately and included a distinct, highly proliferative cluster of CD8 T cells, a finding corroborated by bulk RNA-sequencing and flow cytometry. Although TS/A tumors do not respond to anti-PD1 alone, ENT-induced changes in CD8 T cell phenotype sensitized tumors to PD1 blockade, leading to tumor rejection in most mice when both agents were timed appropriately. Patient tumors, however, have often passed this window to intervene; thus, we devised a tripartite strategy to “reset the clock”. Treating first with an oncolytic virus to liberate new antigens and stimulate new tumor-specific CD8 T cells, then with ENT and anti-PD1 at the right times significantly impaired growth of late-stage tumors and even led to rejection. Our findings show that precisely timed HDAC inhibition generates highly proliferative and strongly cytotoxic CD8 T cell populations whose functions can be further elaborated with correctly timed checkpoint blockade. Resetting the clock using a tumor-lytic strategy then renders this a potent immunotherapy platform." @default.
- W4313365540 created "2023-01-06" @default.
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- W4313365540 date "2019-05-01" @default.
- W4313365540 modified "2023-09-26" @default.
- W4313365540 title "Precisely timed histone deacetylase inhibition creates a highly proliferative intratumoral CD8 T cell population and sensitizes tumors to checkpoint blockade" @default.
- W4313365540 doi "https://doi.org/10.4049/jimmunol.202.supp.195.7" @default.
- W4313365540 hasPublicationYear "2019" @default.
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